Treatment of depression with 3-substituted amino-2-phenylpropiophenones



United States Patent TREATMENT OF DEPRESSION WITH 3-SUBSTI- TUTED AMINO-Z-PHENYLPROPIOPHENONES Corris M. Hofmann, Bound Brook, N.J., Eugene N. Greenblatt, Spring Valley, N.Y., and Sidney R. Safir, River Edge, N.J., assignors to American 'Cyanamid Company, Stamford, Conn., a corporation of Maine No Drawing. Filed Nov. 17, 1967, Ser. No. 683,814

Int. Cl. A61k 27/00; C07c 85/00, 87/00 U.S. Cl. 424-330 9 Claims ABSTRACT OF THE DISCLOSURE This invention describes the preparation of 3-substituted amino-2-phenylpropiophenones by reacting a substituted desoxybenzoin with formaldehyde and subsequently with an amine, and a method of using the compounds for their central nervous system (CNS) anti-depressant activity.

DESCRIPTION OF THE INVENTION This invention relates to new compositions of matter. More particularly, it relates to compositions containing as an active component, 3 substituted amino Z-phenylpropiophenones and salts thereof With a pharmaceutically acceptable carrier, and methods of administering said compositions.

The physiologically active components of the present compositions may be illustrated by the following formula:

wherein R and R are selected from the group consisting of hydrogen, lower alkyl and cyclo lower alkyl, and X, Y

are selected from the group consisting of hydrogen, lower.

alkyl, lower alkoxy and halo, and the non-toxic salts thereof.

The active components of the compositions of this invention as bases are low melting solids or colorless liquids and the salts such as the hydrochloride salts are white crystalline compounds. 1

The active components of the compositions of this invention can be prepared by reacting a suitably substituted desoxybenzoin with formaldehyde in a polar solvent such as boiling mechanol or ethanol in the presence of a catalytic amount of a base, as for example, piperidine. The resulting substituted methylene desoxybenzoin is added to a liquid amine with or without a solvent such as ether, a lower alkanol or benzene. After removal of the excess amine, the resulting S-substituted amino-Z-phenylpropiophenones can be isolated as oils or low melting solids, or

"ice

converted into their solid salts. The following equation illustrates the process described above.

The active components of the present invention are physiologically active in warm-blooded animals as antidepressants or stimulants. The dosage of the compounds of this invention will depend on the route of administration, age, weight, and condition of the warm-blooded animal. A total daily dose of from 1 mg. to about 200 mg. per kilogram of body weight given singly or in divided dosage several times daily embraces the effective range of treatment of most conditions for which the compounds are useful. A dosage unit of 10 mg. to mg. is usually suflicient for daily treatment. Parenteral administration generally requires smaller does than oral administration.

One of the criteria for assessing antidepressant activity is the inhibition of depression of exploratory behavior (in mice) induced by 2 oxo 3 -isobutyl-9,10'-dimethoxy 1,2,3,4,6,7 hexahydro[11,bI-l]benzo [a] quinolizine (tetrabenazine). Untreated mice, when placed in the center of a horizontal disc, will walk rapidly to the edge of the disc and peer over the edge. A reference depressant agent, such as tetrabenazine, will completely suppress this exploratory behavior. However, exploratory behavior is restored to mice which have been treated with one of the active components of this invention priorto treatment with 2 oxo 3-isobutyl-9,IO-dimethoxy-LZ, 3,4,-6,7 hexahydro[11,bH]benzo[a] quinolizine (tetrabenazine). A clinically used reference antidepressant agent, such as imipramine, 5 (2-dimethylaminopropyl)- tive components of this invention show this antidepressant activity.

TABLE I.ACTIVITY OF COMPOUNDS IN PREVENTING TETRABENAZINE-INDUCED DEPRESSION IN MICE II CCHCH:N -HC1 Lowest efiective dose, mg X Y R R kg. i p

H H H H 3. 125 H H H CH3 0. 78 H H CH CH 3. 125 H H H CzHs 3. 125 H H H n-C H 6. 25 H H H A 6. 25 H p-Cl H CH 1. 56 H p-O CH H CH3 6. 25 12-01 H H GHQ 25 H H H i-C H7 3. 125 H p-CH H CH; 1 25. -CH3 p-CH; H CH 1 25. 0 Impriamine 1. 25

1 Succinate salt.

Another test which has been used to demonstrate antidepressant activity is the ability to reverse the hypo thermia in mice caused by reserpine. (a) Reports by Garattini, S., et al.: J. Pharm. Pharmacol., 14, 509 (1962); (b) Jori A. and Garattini, S. ibid. 17, 480 (1965); (c) Jori A., et al.: ibid., 18, 326 (1966) discuss the observation that agents which are antidepressant also reverse the hypothermia caused by reserpine. Two groups of 10 mice are treated with reserpine (solubilized with propylene glycol and citric acid) at a dose of mg./kg. intraperitoneally. Eighteen hours later, at which time the mean rectal temperature has been reduced to F., one group is treated with one of the components of the present invention at a dose of 10 mg./kg. intraperitoneally and the other group is treated with starch at a dose of 0.2 ml./ g. body weight. Rectal temperatures are recorded by the use of a tri-R-Electronic thermometer using a 16 gauge probe inserted 3 cm. into the rectum. Two hours after treatment with the active components of the present invention, the hypothermic effects are significantly reversed as shown in the following Table II.

TABLE II.REVERSAL O13 HYPOTHERMIC EFFECTS OF RESERPINE IN MICE Rectal Temp., F. Reserpine +3-substituted amino-2-phenylpropiophenone (10 mg./kg. LP.)

11-C3H1 Impriamine (45 mgJkg. I. P.)

Rectal temp., F. Reserpine+Starch (5 mgJkg. LP.)

lant and antidepressant activity, it shows depressant activity, one, by protecting animals against convulsive seizures caused by strychnine and two, by reducing their ability to traverse a horizontal rod in a normal manner. This combination of depressant and stimultant-antidepressant activity indicates a wide range of therapeutic utility in mental disorders of various types, for example, in the management of depressive states, in the treatment of convulsive disorders such as epilepsy, and in the alleviation of anxieties. One measure of depressant activity is the ability to prevent convulsive seizures in Warm-blooded animals, e.g., mice, caused by strychnine sulfate. Graded dose levels of the compounds are administered intraperitoneally in a 2% aqueous starch medium to groups of 10 mice at each dose. Strychnine sulfate, dissolved in aqueous saline is administered subcutaneously at doses estimated to cause tonic extensor seizures in of the mice (0.82 milligram per kilogram of body weight). Strychnine is administered 30 minutes after drub treatment. The median effective dose is calculated by the method of Litchfield, I T. & Wilcoxon, F., A Simplified Method of Evaluation, Dose-Effect Experiments, Journal of Pharmacology & Experimental Therapeutics, volume 96, pp. 99-113 (1949).

The dose of 3-methylamino-2-phenylpropiophenone hydrochloride which protects 50 percent of the mice from convulsive seizures caused by strychnine sulfate is 6 milligrams per kilogram intraperitoneally.

Another measure of depressant activity is the ability to protect against seizures produced by electroshock.

Compounds are administered to groups of 10 mice at a dose of 50 mg./kg. Thirty minutes later mice are subjected to maximal electroshock (60 cycle, 50 ma., 0.2 second) via corneal electrodes. If less than 5 mice show protection against tonic extensor seizures, the compound is considered inactive. If 5 or more mice are protected, at least 2 more graded doses are administered to groups of 10 mice each and a median effective dose estimated. The compound 3-amino-2-phenylpropiophenone hydrochloride shows a median effective dose for protection against electroshock seizures of 16.5 mg./kg. The compound 3-ethylamino-2-phenylpropiophenone hydrochloride shows a median effective dose for protection against electroshock seizures of 12.5 rng./kg.

A third measure of depressant activity is the loss of ability of Warm-blooded animals, such as mice, to traverse a horizontal rod. Groups of 10 mice are treated at a dose of 100 mg./kg. and are tested at 15 and 30 minutes after treatment. If 5 or more mice lose the ability to traverse the rod, groups of 6 mice are then treated with at least two more graded doses, and a median effective dose is estimated. The median effective dose for 3-methylamino 2-phenylpropiophenone hydrochloride is 23 mg./kg.

DETAILED DESCRIPTION The examples which follow describe the preparation of the active components of the present invention and their use in formulations of representative pharmaceutical preparations.

EXAMPLE 1 Preparation of 3-ethylamino-2-pheny1propiophenone hydrochloride Ten grams of methylenedesoxybenzoin is added to 20 ml. of liquid ethylamine and the solution is stirred for 1 hour. Ether is added and the solution is evaporated to remove the excess ethy1an1ine This gives 3-ethylamino-2- phenylpropiophenone as an oil hydrochloride, as a while solid. Recrystallization from acetone-ether yields the product, melting point 116.5- 119 C., dec.

EXAMPLE 2 Preparation of 3-propylamino-2-phenylpropiophenone hydrochloride Following the procedure of Example 1 and using npropylamine in place of ethylamine, the product 3-propylamino-2-phenylpropiophenone is obtained as a colorless oil, which is converted, as in Example 1, to a white crystalline hydrochloride, melting point 154.5-157" C., dec.

EXAMPLE 3 Preparation of 3-cyclopropylamino-2-phenylpropiophenone hydrochloride When the procedure of Example 1 is followed using cyclopropylamine in place of ethylamine, the product 3- cyclopropylamino-Z-phenylpropiophenone is obtained. The product is converted to the hydrochloride which when recrystallized from chloroform-ethyl acetate, is a white solid, melting point l47150 C., dec,

EXAMPLE 4 Preparation of 4-chloro-3-methylamino-2-phenylpropiophenone hydrochloride This compound is prepared by adding 11.6 grams of 2- phenyl-4-chloroacrylophenone to 15 ml. of liquid methylamine using the procedure described in Example 1. The product, 4-chloro 3 methylamino-2-phenylpropiophenone, is converted to the hydrochloride, a while solid, melting point 166-168 C., dec.

EXAMPLE 5 Preparation of 3-methylamino-2-(p-methoxyphenyl) propiophenone hydrochloride When 17 grams of 2- (p-methoxyphenyl)acrylophenone is added to 30 ml. of liquid methylamine following the procedure described in Example 1, the product, 3-methylamino2-(p-methoxyphenyl)propiophenone is converted to the hydrochloride, a white solid, melting point 148 151 C., dec, (from a mixture of methanol and ether).

EXAMPLE 6 Preparation of 2-(p-chlorophenyl)acrylophenone A mixture of 46 grams of p-chlorobenzyl phenyl ketone, 480 ml. of methanol, 50 ml, of 37% formaldehyde and 1 ml. of piperidine is stirred and refluxed for 18 hours. The solution is filtered and the filtrate is diluted with 200 ml. of water. The mixture is extracted with methylene chloride and the extracts are washed with dilute sulfuric acid, sodium bicarbonate and water. The methylene chloride extract is then dried and evaporated to give the product, Z-(p-chlorophenyl)acrylophenone as a colorless oil (strong carbonyl absorption at 599 EXAMPLE 7 Preparation of 3-methylamino-2- (p-chlorophenyl) propiophenone hydrochloride When 40 grams of Z-(p-chlorophenyl)acrylophenone is added to 60 ml. of liquid methylamine following the procedure described in Example 1, the product 3-methylamino-2-(pchlorophenyl)propiophenone is converted to the hydrochloride, a White solid, After recrystallization from a mixture of chloroform and ethyl acetate, the product melts at 153.5158.5 C., dec.

,EXAMPLE 8 Preparation of 3-methylamino-2-phenylpropiophenone succinate A solution of 1 gram of 3-methylamino-2-phenylpropiophenone in ethyl alcohol is added to an alcoholic solution of succinic acid. The resultant solution is allowed to stand for several hours. The 3-methylamino-2-phenylpropiophenone succinate slowly separates as a White crystalline solid.

EXAMPLE 9 Preparation of 3-ethylamino-2-phenylpropiophenone fumarate An alcoholic solution of 3-ethylamino-Z-phenylpropiophenone is added to an alcoholic solution of fumaric acid. The resultant solution is cooled, and the 3-ethylamino-2- phenylpropiophenone fumarate separates as a white crystalline solid.

EXAMPLE 10 Preparation of 3-propylamino-Z-phenylpropiophenone maleate An alcoholic solution of 3-propylamino-2-phenylpropiophenone is treated with an alcoholic solution of maleic acid. The resultant solution is cooled, and the 3-propylamino-2-phenylpropiophenone maleate separates as a white crystalline solid.

EXAMPLE 11 Preparation of 2-(p-tolyl)-acrylophenone 0&0 605p) EXAMPLE 12 Preparation of 3-methylamino-2-(ptolyl)- propiophenone succinate 2-(p-tolyl)-acrylophenone (19 g.) is added to methylamine ml.). After stirring for 1 hour, the excess amine is evaporated under reduced pressure at room temperature. The residual oil is dissolved in ether and the basic portion precipitated with hydrogen chloride gas. After decanting the ether, the hydrochloride is dissolved in water, layered with ether, and converted to the free base by addition of dilute aqueous sodium hydroxide. The aqueous layer is extracted once more with ether, and the combined dried (magnesium sulfate) ethereal solutions evaporated under reduced pressure at room temperature. The residual 3-methylamino-2-(p-tolyl)propiophenone is converted to the succinate and the latter crystallized from methanol (melting point 136137 C.).

EXAMPLE 13 Preparation of 2- (p-tolyl -4'-methylacrylophen0ne p-Methylbenzyl-p-tolylketone (44.8 g.) is dissolved in methanol 160 cc.). Formaldehyde (37%, 50 ml.), acetic acid (1 ml.), and piperidine (1 ml.) are added and the solution refluxed for 4 hours. After cooling, water (200 ml.) is added and the solution is extracted with methylene chloride (150 ml.) three times. The organic layer is rinsed with sulphuric acid (2 N, 50 ml.), dilute sodium bicarbonate (50 ml.), and water. The dried (magnesium sulfate) solution is evaporated to give 2-(p-tolyl)-4-methylacrylophenone as an oil which solidifies upon standing ()\C=O=6.05, melting point 46 49.5 C.).

EXAMPLE 14 Preparation of 3-methylamino-2- (p-tolyl)-4-methylpropiophenone succinate Z-(p-tolyl)-4'-methylacrylophenone (20 g.) is added to liquid methylamine ml.). The solution is stirred for 2 hours, and the excess amine is then evaporated at room temperature. The residual material is dissolved in ether and the basic portion precipitated with hydrogen chloride gas. After decanting the ether, the hydrochloride is dissolved in water, layered with ether and converted to the free base by addition of dilute aqueous sodium hydroxide. The aqueous layer is extracted once more with ether, and the combined dried (magnesium sulfate) ethereal solutions evaporated under reduced pressure at room temperature. The residual 3-methylamino-2-(ptolyl)-4-methylpropiophenone is dissolved in ethanol and converted to the succinate salt by addition of an ethanolic solution of succinic acid. Crystallization from ethanol gives 3-methylamino-2-(p-tolyl)-4-methylpropiophenone succinate as a white crystalline solid, melting point 130- 132 C.

EXAMPLE 15 The present compounds can be dispensed in dosage unit forms such as hard shell capsules or soft shell capsules. A formulation found useful in the preparation of such capsules is as follows:

Grams 3-methylamino-2-phenylpropiophenone hydrochloride 2.0

Lactose, U.S.P. 300 Magnesium stearate (0.5%) 3.125

The formulation is thoroughly mixed and placed as equal quantities in 100 capsules.

EXAMPLE 16 The following example represents a formulation useful in preparing tablets. These tablets can be prepared with sufficient active ingredients for a one third days use of about 50 mg. Larger tablets can be scored and divided into halves or quantities to be .given one to four times a day. Obviously also smaller tablets can be used in multiple doses to obtain the daily amount of active material. The following formulation has been useful.

3-dimetl1ylamino-2-phenylpropiophenone hydrochloride 50 Corn starch 210 Methyl cellulose 400 350 Magnesium stearate 1% 182 Total 792 The above tablet contains 50 mg. of drug which is usually given three to six times a day to obtain about the minimum amount of drug per day for a warm-blooded animal of 60 kg.

EXAMPLE 17 The compounds of the present invention can also be given in the form of tablets containing other formulations as follows:

Per tablet, grams 3-amino-2-phenylpropiophenone hydrochloride 0.05

Corn starch 0.3

Ethyl cellulose N/l 0.005

Magnesium stearate 1% 0.0016

Total .3566

8 EXAMPLE 1s The compounds of the present invention can be given intramuscularly orsubcutaneously in the following formulation:

3 ethylamino-2-phenylpropiophcnone hydrochloride 2,500 Sodium carboxymethylcellulose 10 Sodium chloride 9 Tween 1 Benzyl alcohol 9 Sterile water to make 50 ml.

This preparation will contain 50 mg./ml. of the active compound.

EXAMPLE 19 The compounds of the present invention can be given parenterally in the form of parenteral suspensions such as the following:

Pyrogen-free distilled water to make 100.0 ml.

Each milliliter would contain from 20 mg. to 50 mg. of drug. Obviously, other ingredients can be used in place of the above to prepare desired suspensions. For example, as surfactants in place of polysorbitan 80, ethylene oxide or polyoxypropylene base can be used, and other suspending agents such as carboxymethylcellulose, methylcellulose and gelatin can be used. Other salts than sodium chloride can be used such as sodium phosphates. While benzyl alcohol is a desirable preservative, others can be used such as parabens, chlorobutanol, etc. Also, in place of polyethylene glycol 4000, other vehicles can be used such as polyethylene glycol 400.

What i claimed is:

1. The process of producing a therapeutically desirable effect on the central nervous system of warm-blooded animals for the therapeutic treatment of depression which comprises administering internally to warm-blooded animals an antidepressant amount of an amino-Z-phe'nylpropiophenone of the formula:

wherein R is hydrogen and R is selected from the group consisting of hydrogen, lower alkyl and cyclo lower alkyl, and X, Y are selected from the group consisting of hydrogen, lower alkyl, lower alkoxy and chloro, or the non-toxic salts thereof, and a pharmaceutically acceptable carrier therefor.

2. The process according to claim 1, in which the amino-2-phenylpropiophenone is 3-ethylamino-2-phenylpropiophenone.

3. The process according to claim 1, in which the amino-Z-phenylpropiophenone is 3-propylamino-2-phenyL propiophenone.

4. The process according to claim 1, in which the amino-2-phenylpropiophenone is 3-methylamino-2-phenylpropiophenone.

5. The process according to claim 1, in which the amino-2 phenylpropiophenone is 3-methylamino-2-(pmethoxy phen yl -propiophenone.

6. The process according to claim 1, in which the 10 3-methylamino-2- (p is 3-isopropyl-2 phenyl- 5 tolyl)propiophenone.

References Cited UNITED STATES PATENTS 8/1965 Huebner.

OTHER REFERENCES Chem. Abst. 59, Subj. Index 1-2, p. 19575, (1963).

ALBERT T. MEYERS, Primary Examiner 5 STANLEY I. FRIEDMAN, Assistant Examiner 

